Our group has described a pathway resulting through the activation of L DNase II, the LEI derived DNase II . The activation of this DNase II was very first discovered in lens, all through chick lens differentiation , that is an apoptosis related cellular process . The activation of this enzyme has also been noticed in other designs, just like neural apoptosis throughout retina development , corneal endothelial cell death throughout graft rejection or in cell culture . Past research demonstrated that caspases don’t participate in L DNase II activation ; LEI L DNase II is then classified between the caspase independent pathways . L DNase II activation strongly depends upon the apoptotic stimulus received from the cell. Indeed, metabolic worry is prone to induce LEI’s transformation into L DNase II, while genotoxic stress is not. As an example, LEI L DNase II pathway is activated early through HMAinduced apoptosis, HMA staying responsible of an acidification with the intracellular pH , though other stimuli, like etoposide, are usually not able to induce this transformation . The L DNase II pro apoptotic result in HMA induced apoptosis was confirmed by overexpression experiments .
These experiments also display that LEI protects cells from etoposide induced apoptosis . On this paradigm LEI is just not transformed into L DNase II and apoptosis is mediated by caspases . Therefore, LEI L DNase II behaves being a two edge sword: LEI has an anti apoptotic exercise but L DNase II includes a professional apoptotic activity. Proteasome Inhibitor LEI belongs to the ovalbumin subgroup of serpins , also termed Clade B. Most of these serpins can inhibit target proteases and current diversified functions . Some regulate lysosomal proteinases , monocyte granulocyte proteinases , fibrinolysis or bone marrow differentiation . Other folks are tumor suppressors or are implicated in angiogenesis . Moreover, numerous serpins can inhibit apoptosis: the viral serpin Crm A inhibits Fas or TNFa induced apoptosis . Likewise, overexpression of PAI or PI protects cells from TNFa or granzyme B induced apoptosis , respectively. In accordance to these data it isn’t surprising that LEI in its native form has anti apoptotic properties.
On the other hand, the molecular motive of this apoptotic action is not really known. In this post we investigate the basis in the anti apoptotic exercise of LEI in etoposide induced apoptosis and display that it is mediated via the inhibition of cathepsin D. The anti MK 801 apoptotic action of LEI is associated with its anti protease action For you to verify in the event the anti protease action of LEI was associated with cell protection just after an etoposide anxiety, we launched a point mutation within the hinge area of LEI . We transformed an alanine in place P of LEI into threonine . This mutant is shown to have a decreased anti protease activity .